Histone deacetylases (HDACs) are regarded as highly attractive targets for cancer drug discovery. Hyperacetylation induced by HDAC inhibitors leads to changes in gene expression and functional modifications of non-histone proteins, thereby triggering antitumor pathways. Well-characterized HDAC inhibitors typically contain three structural features useful for activity: an aromatic cap group, an aliphatic linker chain and a zinc binding group (ZBG). Based on molecular modeling studies involving the histone deacetylase-like protein (HDLP), these molecules appear to bind in a pocket in the HDAC active site that includes a channel region flanked by a zinc ion on one end, and a region that binds the cap group on the other end. In this model, the aromatic group and aliphatic chain of the inhibitor are buried in the enzyme pocket in such a way that the metal binding moiety coordinates the catalytic zinc ion. Structural studies to identify novel HDAC inhibitors has focused primarily on modifications to the aliphatic linker or the aromatic cap group, while less attention has been paid to the metal binding group, which is typically either a hydroxamic acid or a benzamide. However, hydroxamates suffer from low bioavailability and significant off-target effects that limit their clinical use. Similarly, benzamides contain an aniline moiety that may generate toxic metabolites in vivo.
There is a need, therefore, for the development of new HDAC inhibitors with ZBGs that possess minimal toxicity and improved pharmacokinetic profiles.